RU-486

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Anti-abortion extremists may be preventing development of and access to a drug which potentially reduces HIV replication and may be useful in the treatment of lipodystrophy ("crix belly," "buffalo hump") which is experienced by many people with HIV.

RU486 (also known as mifepristone), the oral drug used for non-surgical abortions developed in France, shows some promise as an anti-viral and as a treatment for the problems with fat metabolism which particularly seem to affect people taking protease inhibitors.

But we don't know enough yet about how HIV causes disease to warrant human trials of the drug. And there is another drug, currently in clinical trials, which doesn't have the abortion baggage that RU486 does but may have similar effects.

Here's what is known: In 1995, David Weiner and his colleagues at the University of Pennsylvania published a paper in the Proceedings of the National Academy of Sciences which detailed how a class of receptors found in the human body and brain have some interaction with a protein made by HIV.

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These receptors are normally occupied by chemicals called "glucocorticoids," which include stress hormones like cortisol and sex hormones like progesterone. RU486 blocks these receptors -- and also seems to block a protein made by HIV to regulate its life cycle. Weiner says the data isn't yet clear as to whether the HIV protein actually occupies glucocorticoid receptors in the body -- and what effect it has if it does. But in the test tube, RU486 reduces virus production by 70% in macrophages (a type of immune cell).

Weiner cautions that the RU486 formulation used in his research is different from the one designed for use in abortions and that people should not take (if they can even manage to get) the currently available drug to try to treat themselves. "The abortifacient [RU486] includes two different drugs and the drug we used in our lab we made ourselves," he said. "No tests have yet been done on humans and that would be premature at this point," he added.

Increases in glucocorticoids have also been linked to increased risk of Kaposi's Sarcoma (KS). Canadian researchers studied cells from people with HIV and KS and found that drugs which increase the release of glucocorticoids (such as dexamethasone) make both conditions worse by increasing the proliferation of infected cells. Treatment with RU486 completely blocked this effect in the cultured cells.

Researchers believe that RU486 may be useful in treating lipodystrophy because of the similarity between this condition and a disorder called "Cushing's syndrome." In fact, patients with lipodystrophy were often believed to have Cushing's syndrome at first because it also produces increases in waist size, buffalo hump at the back of the neck and higher cholesterol and triglycerides.

Cushing's syndrome is characterized medically by a higher than normal level of the stress hormone cortisol, often caused by a tumor in the adrenal glands. Cortisol has immuno-suppressant effects as well. RU486 has been studied in the treatment of Cushing's syndrome, which can be fatal. Case reports suggest that some people with inoperable tumors causing Cushing's syndrome not only experienced complete reversal of the symptoms, but also control over the disease. In 1990, two people whose lives were saved by this treatment testified before Congress to push for approval of the drug.

When the abnormalities which usually cause Cushing's syndrome were ruled out in people with HIV, researchers knew that the lipodystrophy people were experiencing could be related either to HIV infection itself or to medications the people were taking. Lipodystrophy does seem more likely amongst people on protease inhibitors (some 75% of people on PI regimens will experience some form of it after two years on these drugs), but some people with HIV who are not taking PI's have also developed similar symptoms.

People with HIV have also long been known to have problems with blood cortisol levels and cortisol regulation (the levels are supposed to change at certain times of day), and these seem to be thrown off even further as HIV progresses. Perhaps this not only helps HIV to kill more cells, but also helps cause lipodystrophy? Perhaps protease inhibitors somehow advance the process that causes lipodystrophy, even while reducing levels of the virus itself.? Perhaps this is caused by interactions between HIV proteins and glucocorticoid receptors?

RU486 research could help answer these questions and possibly offer an important new anti-viral treatment option for people with HIV, and a new way of fighting the often disfiguring lipodystrophy. But abortion politics may stand in the way.

The FDA has issued an "approvable" letter for the drug, but it is not yet actually available in the U.S. Because of fears about anti-abortion violence, importation for personal use, while technically possible, is highly difficult because foreign sources won't make it available to Americans. And there is no manufacturer currently producing the type used for HIV experiments in Weiner's lab.

An American manufacturer, the Population Council, expects to have the abortifacient form of the drug available to researchers and for compassionate access early in 1999.

Long term effects of the drug have been described in Nature Medicine as "slight to moderate," although some patients may develop problems due to elevated cortisol and ACTH (a hormone) in the blood, which can be extremely serious, even fatal.

Dr. Donald Kotler of St. Lukes/Roosevelt Hospital says that before RU486 trials can be considered, more studies are needed on the relationship between cortisol and lipodystrophy. "If cortisol doesn't cause lipodystrophy but is just related to it, there would be no reason to study RU486," he said.

"We know that there is some problem in HIV-infected people with cortisol -- with synthesis, secretion or the sensitivity of the body to it." he said. "I have some evidence of hypersecretion in lipodystrophy, not huge, and it doesn't mean that it causes it, but I do have some evidence of it. We need more research."

Kotler also points out that HIV lipodystrophy is similar to a fat metabolism problem called "Syndrome X," which is linked with early heart attacks and strokes. "Within a few years we may see thousands of people having heart attacks at age 35 if we don't figure out how to do something about this," he says.

Another glucocorticoid blocker, which doesn't have the political baggage that RU486 does, may be the answer. A drug called Anticort, manufactured by a Las Vegas company with the awkward name Steroidogenesis Inhibitors, has just been approved by the FDA to enter phase 1B and 2A trials for HIV treatment. This means that the drug has passed safety tests, but still needs to be tested to see which dose might be most effective.

A paper presented at the 1996 AIDS conference in Vancouver of an open trial of the drug found that T-cells increased by 35-40 cells per month in patients on the drug and that CD8 cells came back to normal levels. Also, according to author Dr. Alfred Sapse, who works for the company, "It dramatically reduced depression." Sapse says this isn't surprising because high cortisol levels are linked with depression in general.

The AIDS Research Alliance in Los Angeles is currently enrolling patients for the dosage trials. For more information, contact Dr. Steven Brown at 310-558-2423. The trials should start this spring, according to Dr. Sapse.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

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